Jason C. Hedges

A Role for p38MAPK/HSP27 Pathway in Smooth Muscle Cell Migration

Smooth muscle cells are exposed to growth factors and cytokines that contribute to pathological states including airway hyperresponsiveness, atherosclerosis, angiogenesis, smooth muscle hypertrophy, and hyperplasia. A common feature of several of these conditions is migration of smooth muscle beyond the initial boundary of the organ. Signal transduction pathways activated by extracellular signals that instigate migration are mostly undefined in smooth muscles. We measured migration of cultured tracheal myocytes in response to platelet-derived growth factor, interleukin-1β, and transforming growth factor-β. Cellular migration was blocked by SB203580, an inhibitor of p38MAPK. Time course experiments demonstrated increased phosphorylation of p38MAPK. Activation of p38MAPK resulted in the phosphorylation of HSP27 (heat shockprotein 27), which may modulate F-actin polymerization. Inhibition of p38MAPK activity inhibited phosphorylation of HSP27. Adenovirus-mediated expression of activated mutant MAPK kinase 6b(E), an upstream activator for p38MAPK, increased cell migration, whereas overexpression of p38α MAPK dominant negative mutant and an HSP27 phosphorylation mutant blocked cell migration completely. The results indicate that activation of the p38MAPK pathway by growth factors and proinflammatory cytokines regulates smooth muscle cell migration and may contribute to pathological states involving smooth muscle dysfunction.

Improved fertility preservation care for male patients with cancer after establishment of formalized oncofertility program

PURPOSE Survival to reproductive age among men with cancer has steadily increased and yet cancer therapy and cancer itself may carry the risk of infertility. Since 2006, we have used a formalized fertility preservation program with expedited fertility care at our institution. We assessed the impact of this program by comparing the frequency of sperm cryopreservation and patient characteristics before and after its implementation. MATERIALS AND METHODS Men 18 to 55 years old diagnosed with cancer at our institution from 2002 to 2010 were included in our study. We retrospectively reviewed patient charts to identify those who were offered and subsequently used fertility preservation services before and after program formalization. RESULTS From 2002 to 2010 at our institution 4,818 men 18 to 55 years old were diagnosed with cancer, of whom 411 were offered fertility preservation consultation and 249 underwent sperm cryopreservation. Since program implementation, the annual number of men receiving fertility preservation consultation and undergoing sperm cryopreservation increased by 2.4 and 2.7-fold, respectively, while the total number diagnosed with cancer remained fairly constant. Upon substratifying patients into the more conventional reproductive age range of 18 to 40 years 23.4% of all men with cancer in this group were offered consultation before formalization vs 43.3% after formalization (p <0.05). The overall sperm use and discard rates were 8.4% and 14.8%, respectively. CONCLUSIONS A formalized institutional fertility preservation program significantly increased the overall number and percent of male patients with cancer who received fertility preservation consultation and pursued sperm cryopreservation. These increases were seen in men with all types of cancer and across all demographics assessed at our institution.

Poly-IC preconditioning protects against cerebral and renal ischemia-reperfusion injury

Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

Prostate cancer diagnosis is associated with an increased risk of erectile dysfunction after prostate biopsy.

There have been several studies that have suggested there may be a relationship between prostate biopsy and erectile function and LUTS. Previous studies have suggested a specific association between the type of local anaesthesia administered and/or the number of biopsies performed. Other studies have suggested an exacerbation of LUTS after prostate biopsy. The present study identifies a positive cancer diagnosis as a novel characteristic that may explain a relationship between biopsy and worsening erectile function.

Higher Outcomes of Vasectomy Reversal in Men with the Same Female Partner as Before Vasectomy

PURPOSE We reviewed fertility outcomes of vasectomy reversal at a high surgical volume center in men with the same female partner as before vasectomy. MATERIALS AND METHODS We retrospectively studied a prospective database. All vasectomy reversals were performed by a single surgeon (EFF). Patients who underwent microsurgical vasectomy reversal and had the same female partner as before vasectomy were identified from 1978 to 2011. Pregnancy and live birth rates, procedure type (bilateral vasovasostomy, bilateral vasoepididymostomy, unilateral vasovasostomy or unilateral vasoepididymostomy), patency rate, time from reversal and spouse age were evaluated. RESULTS We reviewed the records of 3,135 consecutive microsurgical vasectomy reversals. Of these patients 524 (17%) who underwent vasectomy reversal had the same female partner as before vasectomy. Complete information was available on 258 patients (49%), who had a 94% vas patency rate. The clinical pregnancy rate was 83% by natural means compared to 60% in our general vasectomy reversal population (p <0.0001). On logistic regression analysis controlling for female partner and patient ages, years from vasectomy and vasectomy reversal with the same female partner the OR was 2 (p <0.007). Average time from vasectomy was 5.7 years. Average patient and female partner age at reversal was 38.9 and 33.2 years, respectively. CONCLUSIONS Outcomes of clinical pregnancy and live birth rates are higher in men who undergo microsurgical vasectomy reversal with the same female partner. These outcomes may be related to a shorter interval from vasectomy, previous fertility and couple motivation.

Impact on Pregnancy of Gross and Microscopic Vasal Fluid during Vasectomy Reversal.

PURPOSE We compared fertility outcomes with gross and microscopic fluid findings at vasectomy reversal at a high volume vasectomy reversal center. MATERIALS AND METHODS A retrospective study of a prospective database was performed. All vasectomy reversals were performed by a single surgeon (EFF) between 1978 and 2011. The clinical pregnancy rate was self-reported or determined via patient mailers. Patient and operative findings were determined through database review. We classified vasal fluid as opalescent, creamy, pasty or clear. Intraoperative light microscopy was used to determine if sperm or sperm parts were present and if they were motile. Multivariate analysis was performed evaluating patient age, partner age, years after vasectomy, type of surgery, and gross and microscopic fluid analysis. RESULTS A total of 2,947 microsurgical vasectomy reversals were reviewed after we excluded reversals performed for post-vasectomy pain. We determined the pregnancy status of 902 (31%) cases. On univariate analysis with respect to pregnancy the presence of motile sperm at vasovasostomy neared statistical significance (p=0.075) and there was no difference between bilateral vs unilateral motile sperm. Gross fluid appearance was not statistically significant but we found the order of pregnancy success to be opalescent, creamy, clear then pasty fluid. On multivariate analysis only female partner age and sperm heads only or no sperm seen on light microscopy had statistical significance (p <0.05). CONCLUSIONS The presence of motile sperm at vasectomy reversal approaches statistical significance on univariate analysis as a factor that affects clinical pregnancy rates. On multivariate analysis female partner age and microscopic findings of sperm heads only or no sperm are inversely related to pregnancy rates. These data will help counsel couples after vasectomy reversal and reinforce the importance of female partner age.

Relating economic conditions to vasectomy and vasectomy reversal frequencies: a multi-institutional study.

PURPOSE It was theorized that the use of permanent contraceptive methods may vary with economic conditions. We evaluated the relationship between vasectomy/vasectomy reversal frequencies at several large referral centers and national economic indicators during 2 recessions spanning 2001 to 2011. MATERIALS AND METHODS We performed an institutional review board approved, retrospective chart review to identify the number of vasectomies/vasectomy reversals per month at several large referral centers from January 2001 to July 2011. The rates of these procedures were pooled, correlated with national economic data and analyzed in a multivariate linear regression model. RESULTS A total of 4,599 vasectomies and 1,549 vasectomy reversals were performed at our institutions during the study period. The number of vasectomies per month positively correlated with the unemployment rate (r=0.556, p<0.001) and personal income per capita (r=0.276, p=0.002). The number of reversals per month negatively correlated with the unemployment rate (r=-0.399, p<0.001) and personal income per capita (r=-0.305, p<0.001). Neither vasectomy nor vasectomy reversal frequency significantly correlated with the inflation rate or the S&P 500®. Regression models confirmed that the unemployment rate explained more of the variance in vasectomy/vasectomy reversal frequencies than other indicators. CONCLUSIONS We noted a correlation between the number of vasectomies/vasectomy reversals performed at our institutions and national economic indicators. The strongest association was with the unemployment rate. This points to the importance of financial pressure on family planning decisions.

Vacuum Therapy for Erectile Dysfunction

Since receiving FDA approval in 1982, vacuum erection devices (VEDs) have benefitted millions of men suffering from erectile dysfunction (ED). Vacuum therapy has since been overshadowed by advances in pharmacologic and surgical therapies for ED; however, there has been a recent resurgence in the popularity of the VED. This is in large part due to its developing role in post-prostatectomy penile rehabilitation. As a treatment for erectile dysfunction, vacuum therapy remains notable as a noninvasive, nonpharmacologic, safe, cost-effective, and efficacious treatment option. This chapter will review the evolution of vacuum therapy as well as its mechanism of action, efficacy, safety profile, and expanding applications beyond the traditional realm of ED.

Bone Saw for Calcified Peyronie's Disease Plaques

OBJECTIVES To determine the incidence of calcified Peyronies disease plaque that cannot be cut with a blade in a 100-case series and to describe the use of a soft tissue-protecting bone saw for plaque incision. METHODS Chart reviews were done of all surgically treated Peyronies disease patients at our center between October 1996 and December 2012. 100 cases were included. We evaluated our novel technique of tissue-protecting bone saw surgical use. RESULTS 100 consecutive patients underwent surgery for Peyronies disease, and 6 required transverse bone saw plaque incision due to the severity of calcification that could not be cut with a blade. Four of those 6 underwent grafting procedures with porcine submucosal intestinal substance (SIS) and 2 underwent placement of inflatable penile prosthesis (IPP) after plaque incision. There were no surgical complications. Both IPP patients had functioning prosthesis 4 and 7.3 years after surgery. One SIS-graft patient required re-operation for more proximal curvature 11 months later and ultimately required multiple plaque incisions and an IPP. CONCLUSION Densely calcified plaques occurred in 6% of a surgical series of Peyronies disease patients. The vibrating bone saw is a novel technique to incise calcified plaques before grafting or IPP placement.

MP60-04 VASAL PROTEIN PROFILE AND MICROSCOPIC SPERM PRESENCE AT TIME OF VASECTOMY REVERSAL

RESULTS: Four weeks after subcutaneous autograft of LSCs in combination with Sertoli and myoid cells in castrate mice, the cells in graft expressed 3B-HSD, SOX-9 and A-SMA. Serum testosterone in castrated mice that received autograft was significantly higher compared to mice that did not receive autograft (22.4þ/-1.9 VS 11.9þ/0.8 Ng/DL, p<0.05). Importantly, mice that received LSC autograft maintained production of LH and FSH with levels higher than mice that received testosterone pellet implant (LH 3.09þ/-1.47 VS 0.01þ/-0.01 ng/ml) (FSH 102.6þ/-28.1 VS 51.7þ/-7.4ng/ml) respectively. Furthermore, T levels consistently increased at 15, 30 and 60 days following subcutaneous autograft (12.01þ/-0.87ng/DL (neg CTL) vs 15.1þ/1.50ng/DL (15 days Autograft) vs 22.26þ/-1.33ng/DL (30 days Autograft) vs 37.3þ/-9.6ng/DL (60 days Autograft)), demonstrating differentiating LSC within the autograft. In addition, we found that levels of 3BHSD were induced upon SAG (DHH inducer) treatment in-vitro conditions. Immunostaining autografts (4 weeks), containing LSCs treated with SAG before subcutaneous implantation, showed higher levels of SOX9, and ASMA. Importantly, T levels were significantly higher (p<0.05) in mice received SAG treated autografts vs negative controls (23.95þ/4.11 Ng/DL vs 11.91þ/-0.80 Ng/DL). Collectively these results establish that Hedgehog signalling induces survival of adjacent testicular cells and regulates graft function. CONCLUSIONS: Our results demonstrate that subcutaneous autograft of LSC in combination with Sertoli cells and myoid cells can increase serum testosterone without inhibiting circulating LH and FSH in castrate mice. Extratesticular LSC appear to be regulated by Hedgehog signalling. Leydig stem cell autograft can a novel therapeutic approach to increase serum testosterone while simultaneously preserving hypothalamic-pituitary-gonadal axis. Factors involved in hedgehog signalling can be utilized to enhance graft efficacy.